This invention relates to heterocyclic vinylic amines reagents useful for the preparation of biocidal polymers. The biocidal polymers are usefull for generating medical and hygienic-use textiles.
Contamination of polymeric materials by microorganisms such as pathogenic bacteria, odor-generating bacteria, molds, fungi and viruses is of great concern in the medical industry, the food and restaurant industries, as well as in consumer products. Survival of microorganisms on polymeric materials and transfer of these microorganisms between patients and health care workers (HCWs) has been demonstrated, and it is widely accepted that hospital gowns, patient drapes, carpeting and bedding materials, etc., can be elements in cross-infections. (see, Lidwell, O. M. et al., J Appl. Bact. 37:649 (1974)); Rubbo, S. D. and Saunders, J., J Hyg. Camb., 61:507 (1963); Ransjo, U., J. Hyg. Camb., 82:369 (1979); and Hambraeus, A., J. Hyg. Camb., 71:799 (1973)). Medical gowns and uniforms currently in use provide barriers for HCWs, but have proven to be ineffectual in studies by numerous researchers. (see, for example, Beck, W. C. and Collette, T. S., Am. J. Surg., 83:125 (1952); Smith, J. W. and Nichols, R. L. Arch. Surg., 126:756 (1991); Lovitt, S. A. et al., Am. J. Infect. Control, 20:185 (1992); Quebbeman, E. J. et al., Annal. Surg., 214:614 (1991); Granzow, J. W. et al., Am. J. Infect. Control, 26:85 (1998)).
The occurrence of contaminated cleaning cloths in domestic applications has also been investigated. Results from several different studies indicate that more than half of the investigated dish cloths and cleaning cloths were contaminated by one or more of the following organisms: Escherichia coli, Staphylococcus aureus, Streptococcus faecahis and Clostridium perfringens (see, Scott, E. et al., J. Hyg. Camb., 89:279 (1982); Tebutt, C. M., J. Hyg. Camb., 97:81 (1986); and Scott, E. et al., J. Appl. Bact., 68:271 (1990)). Further studies show that wiping hard surfaces with contaminated cloths can result in contamination of hands, equipment and other surfaces. (see, Mackintosh, C. A. and Hoffman, P. N. J. Hyg. Camb., 92:345 (1984)).
These findings suggest that biocidal properties should be an effective feature of medical and related healthcare and hygienic-use textiles. In general, hygenic-use textiles are made of synthetic polymers, and polymeric biocides have been reviewed by several researchers recently. (see, Vigo, T. L. (R. B. Seymour and R. S. Porter, Eds.), Manmade Fibers: Their Origin and Development, Elsevier Appl. Sci., p. 214 (1992); Vigo, T. L. (Gebelein, C. and Carraher, C., Eds.), Biotechnology and Bioactive Polymers, Plenum Press, p. 225 (1994); Worley, S. D. and Sun, G., Trends Polym. Sci., 11:364 (1996)).
Among the currently investigated biocidal materials, N-halamines have been shown to provide almost instant and total kill of a wide range of microorganisms. (see, Worley, S. D. et al., Trends Polym. Sci., 11:364 (1996)). There are many advantages associated with using N-halamine structures. First, they are stable in long-term use and storage over a wide temperature range. Second, they are regenerable when activity is lost due to normal use patterns. (see, Sun, G. et al., Polymer, 37:3753 (1996); Worley, S. D. et al., The Polymeric Materials Encyclopedia, 1, A-B, p. 550 (1996); Sun, G. et al. Water Res. Bull., 1996, 32:793 (1996)). More recently, N-halamine materials have been incorporated into cellulose-containing fabrics. (see, Bickert, J. R. et al., International Conference on Safety and Protective fabric ""98, 1998, p 1; Sun, G. et al., Textile Chem. Colorist, 6:26 (1998); Sun, G. et al., Textile Chem. Colorist, 31:21 (1999)). Results indicate that as little as 1% (wt) add-on of halamine structures provides powerful biocidal efficacy (6-7 log reduction) against the most common pathogens, at a contact time of two minutes.
U.S. Pat. No. 5,882,357, issued to Sun et al., on Mar. 16, 1999, discloses durable and regenerable microbiocidal textiles and methods for preparing the same. The microbiocidal textiles are prepared using a wet finishing process to covalently attach a heterocyclic N-halamine to a cellulose-based material or other polymeric material. The biocidal activity of the textiles can be regenerated by washing with a halogenated solution. In addition, U.S. Pat. No. 6,020,491, issued to Wonley et al., on Feb. 1, 2000, discloses cyclic amine monomers and polymers that are used to form biocidal N-halamine polymers. The polymers are useful as disinfectants for potable water, swimming pools, hot tubs, industrial water systems, cooling towers, air-conditioning systems, and the like.
In spite of the advances in the prior art, there remains a need for new monomeric units useful for generating polymers having microbiocidal activity. Polymers that can be used to generate microbiocidal fabrics, rubbers, plastics, paints, coatings, and articles are also needed. The present invention fulfills these and other needs.
In certain embodiments, the present invention provides heterocyclic vinylic amines that can be readily polymerized with most acrylic, substituted-acrylic and vinyl monomers. The polymers thus generated exhibit biocidal efficacy after exposure to a halogen source, such as chlorine bleach. Moreover, their antibacterial properties are durable and regenerable. As such, the present invention provides a compound having the formula 
In Formula I, A is a functional group including, but not limited to, NH, Nxe2x80x94R8 and CR1R2, wherein R8 is a halogen R1 and R2, in Formula I are each a functional group including, but not limited to, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted cycloalkyl, optionally substituted (C1-C6)alkoxy, optionally substituted aryl and optionally substituted heteroaryl.
In an alternative embodiment, R1 and R2 and the carbon to which they are bound, join to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring.
In Formula I, Q is a functional group including, but not limited to, C(O), NH, Nxe2x80x94R9 and CR3R4, wherein R9 is a halogen. R3 and R4, in Formula I are each a functional group including, but not limited to, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted cycloalkyl, optionally substituted (C1-C6)alkoxy, optionally substituted aryl and optionally substituted heteroaryl.
In an alternative embodiment, R3 and R4 and the carbon to which they are bound, join to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring.
In Formula I, X is a functional group including, but not limited to, C(O)xe2x80x94NR5 and CR6R7, wherein R5 is a functional group including, but not limited to, hydrogen, halogen, optionally substituted (C2-C6)alkenyl and optionally substituted (C1-C6)alkyl. R6 and R7, in Formula I, are each a functional group including, but not limited to, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted cycloalkyl, optionally substituted (C1-C6)alkoxy, optionally substituted aryl and optionally substituted heteroaryl;
In an alternative embodiment, R6 and R7 and the carbon to which they are bound, join to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring.
Z, in Formula I, is a functional group including, but not limited to, optionally substituted (C1-C3)alkylene, C(O), or a single bond. When Z is a single bond, a vinyl group is bonded directly to the ring nitrogen.
In another embodiment, the present invention provides a polymer comprising a mixture of monomeric units having the formulae 
In Formula II, A is a functional group including, but not limited to, NH, Nxe2x80x94R8 and CR1R2, wherein R8 is a halogen. R1 and R2, in Formula II, are each a functional group including, but not limited to, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl), optionally substituted cycloalkyl, optionally substituted (C1-C6)alkoxy, optionally substituted aryl and optionally substituted heteroaryl.
In an alternative embodiment, R1 and R2 and the carbon to which they are bound, join to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring.
In Formula II, Q is a functional group including, but not limited to, C(O), NH, Nxe2x80x94R9 and CR3R4, wherein R9 is a halogen.
R3 and R4, in Formula II are each a functional group including, but not limited to, R3 and R4, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted cycloalkyl, optionally substituted (C1-C6)alkoxy, optionally substituted aryl and optionally substituted heteroaryl.
In an alternative embodiment, R3 and R4 and the carbon to which they are bound, join to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring.
In Formula II, X is a functional group including, but not limited to, C(O)xe2x80x94NR10 and CR6R7, wherein R10 is a functional group including, but not limited to, hydrogen, halogen, optionally substituted (C2-C6)alkenyl and optionally substituted (C1-C6)alkyl.
R6 and R7, in Formula II, are each a functional group including, but not limited to, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted cycloalkyl, optionally substituted (C1-C6)alkoxy, optionally substituted aryl and optionally substituted heteroaryl.
In an alternative embodiment, R6 and R7 and the carbon to which they are bound, join to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring.
Z, in Formula I, is a functional group including, but not limited to, optionally substituted (C1-C3)alkylene, C(O), or a single bond.
R11 in Formula II, is a functional group including, but not limited to, hydrogen, halogen, hydroxyl, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarboxyl, aldehydo, amido, aryl and heterocyclyl.
R12 in Formula II, is a functional group including, but not limited to, hydrogen, halogen, hydroxyl, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarboxyl, aldehydo, amido, aryl and heterocyclyl.
R13 in Formula II, is a functional group including, but not limited to, hydrogen, halogen, hydroxyl, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarboxyl, amido, aldehydo, aryl and heterocyclyl.
R14 in Formula II, is a functional group including, but not limited to, hydrogen, halogen, hydroxyl, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarboxyl, aldehydo, amido, aryl and heterocyclyl. The index xe2x80x9cxxe2x80x9d is an integer from 1 to 250 inclusive. The index xe2x80x9cyxe2x80x9d is an integer from 1 to 250 inclusive.
In yet another embodiment, the present invention provides a polymer comprising a polymeric unit of the formula: 
wherein A, Q, X, Z, R1, R2, R3, R4, R6, R7, R8, R9, R10, R11R12, R13, R14, xe2x80x9cnxe2x80x9d and xe2x80x9cyxe2x80x9d have been defined above. In this embodiment. The polymer comprises a least one unit having a dimmer wherein xe2x80x9cnxe2x80x9d is 1 and xe2x80x9cyxe2x80x9d is 1.
In still yet another embodiment, the present invention provides a method for making a polymer, comprising: admixing a compound having the formula 
wherein A, Q, X, Z, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have been defined above, with a with a vinyl monomer in a reaction mixture thereby making a polymer.
In another embodiment, the present invention provides a method for chemically modifying a polymer, comprising: admixing the polymer in a reaction mixture with a compound having the formula he formula 
wherein A, Q, X, Z, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have been defined above, with a vinyl monomer in a reaction mixture thereby chemically modifying the polymer.
In certain aspects, a hydantoin-containing monomer such as 3-allyl-5,5- dimethylhydantoin, are grafted onto a polymer such cotton cellulose, in the presence of a monomeric unit such as acrylonitrile. Thereafter, the hydantoin units in the grafted copolymers are readily converted to N-halamine structures on exposure to a halogenated material (e.g., chlorine bleach). The N-halamine derivatives of the corresponding grafted samples exhibit potent antibacterial properties against microorganisms e.g., Escherichia coli. Moreover, these antibacterial properties are durable and regenerable.
These and other features and advantages will become more apparent when read with the accompanying figures and detailed description that follows.
As used herein xe2x80x9cADMHxe2x80x9d means 3-allyl-5,5-dimethylhydantoin.
As used herein xe2x80x9cAIBNxe2x80x9d means 2,2xe2x80x2-azobisisobutyronitrile.
As used herein xe2x80x9cANxe2x80x9d means acrylonitrile.
As used herein xe2x80x9cBADDxe2x80x9d means 7,8-benzo-1,3-diazasprio[4.5]decane-2,4-dione.
As used herein xe2x80x9cBADDDxe2x80x9d means 7,8-benzo-3-allyl-1,3-diazaspiro[4.5]decane-2,4-dione.
As used herein xe2x80x9cDMHxe2x80x9d means 5,5-dimethylhydantoin.
As used herein xe2x80x9cMMAxe2x80x9d means methyl methacrylate.
As used herein xe2x80x9cPPSxe2x80x9d means potassium persulfate.
As used herein xe2x80x9cVACxe2x80x9d means vinyl acetate.
As used herein, the term xe2x80x9calkylxe2x80x9d denotes branched or unbranched hydrocarbon chains, preferably having about 1 to about 8 carbons, such as, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, octa-decyl and 2-methylpentyl. These groups can be optionally substituted with one or more functional groups which are attached commonly to such chains, such as, hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, heterocyclyl, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form alkyl groups such as trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like.
The term xe2x80x9calkylenexe2x80x9d refers to a divalent alkyl group as defined above, such as methylene (xe2x80x94CH2xe2x80x94), propylene (xe2x80x94CH2CH2CH2xe2x80x94), chloroethylene (xe2x80x94CHClCH2xe2x80x94), 2-thiobutene xe2x80x94CH2CH(SH)CH2CH2, 1-bromo-3-hydroxyl-4-methylpentene (xe2x80x94CHBrCH2CH(OH)CH(CH3)CH2xe2x80x94), and the like.
The term xe2x80x9calkenylxe2x80x9d denotes branched or unbranched hydrocarbon chains containing one or more carbon-carbon double bonds.
The term xe2x80x9calkynylxe2x80x9d refers to branched or unbranched hydrocarbon chains containing one or more carbon-carbon triple bonds.
The term xe2x80x9carylxe2x80x9d denotes a chain of carbon atoms which form at least one aromatic ring having preferably between about 6-14 carbon atoms, such as phenyl, naphthyl, and the like, and which may be substituted with one or more functional groups which are attached commonly to such chains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl, imidazolylmethylphenyl, and the like.
The term xe2x80x9calkoxyxe2x80x9d denotes xe2x80x94ORxe2x80x94, wherein R is alkyl.
The term xe2x80x9camidoxe2x80x9d denotes an amide linkage: xe2x80x94C(O)NHR (wherein R is hydrogen or alkyl).
The term xe2x80x9caminoxe2x80x9d denotes an amine linkage: xe2x80x94NRxe2x80x94, wherein R is hydrogen or alkyl.
The term xe2x80x9ccarboxylxe2x80x9d denotes xe2x80x94C(O)Oxe2x80x94, and the term xe2x80x9ccarbonylxe2x80x9d denotes xe2x80x94C(O)xe2x80x94.
The term xe2x80x9calkylcarbonylxe2x80x9d denote an alkyl group as defined above subsituted with a C(O) group, for example, CH3C(O)xe2x80x94, CH3CH2C(O)xe2x80x94, etc.
The term xe2x80x9calkylcarboxylxe2x80x9d denote an alkyl group as defined above subsituted with a C(O)O group, for example, CH3C(O)Oxe2x80x94, CH3CH2C(O)Oxe2x80x94, etc.
The term xe2x80x9ccarbocyclexe2x80x9d means a cyclic hydrocarbon chain having about 5 to about 8 ring carbons such as cyclopentyl, cylcohexyl, etc. These groups can be optionally substituted with one or more functional groups as defined under xe2x80x9calkylxe2x80x9d above.
The term xe2x80x9chalogenxe2x80x9d includes chlorine, fluorine, bromine, iodine and mixtures thereof
The term xe2x80x9cheterocyclexe2x80x9d means a straight chain or ring system that may contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Non-limiting examples of heterocycle groups include 1-pyrrolyl, 2-pyrrolyl 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pryrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, etc. These groups can be optionally substituted with one or more functional groups as defined under xe2x80x9calkylxe2x80x9d above.
The terms xe2x80x9cantimicrobial,xe2x80x9d xe2x80x9cmicrobicidal,xe2x80x9d or xe2x80x9cbiocidalxe2x80x9d as used herein, refer to the ability to kill at least some types of microorganisms, or to inhibit the growth or reproduction of at least some types of microorganisms. The polymers prepared in accordance with the present invention have microbicidal activity (antimicrobial) against a broad spectrum of pathogenic microorganisms. For example, if the polymer is grafted to a textile, the textiles have microbicidal activity against representative gram-positive (such as Staphylococcus aureus) and gram-negative bacteria (such as Escherichia coli). Moreover, the microbicidal activity of such textiles is readily regenerable.